This invention is related to the naphthyloxyacetic acid derivatives. More particularly, this invention is related to
(1) the naphthyloxyacetic acid derivatives of the formula (I) 
wherein all symbols are the same meaning as hereafter defined, or non-toxic salts thereof, acid addition salts thereof or their hydrates and
(2) a pharmaceutical composition (Prostaglandin E2 (PGE2) antagonists or agonists) which comprises them as an active ingredient.
PGE2 has been known as metabolite in the arachidonate cascade. In addition, the recent progress in the molecule biological technology makes the existence of three PGE2 receptors clear as shown in the following and have been making the relationship between each receptor and appearance of biological activity clear. For example, EP1 receptor may cause contraction of the smooth muscle of digestive canal or bronchus etc. and promote the release of neurotransmitter. The representative activity of EP2 receptor is relaxation of smooth muscle of bronchus or ileum etc. or vasodilatation and reduce of the blood pressure due to relaxation of vascular smooth muscle. As the activity of EP3 receptor, uterine muscle contraction, suppression of gastric acid secretion, inhibition of reabsorption of water and ion by vasopressin in renes, inhibition of fat decomposition in fat tissue, inhibition of release of neurotransmitter and glucose-decomposition by gulcagon in liver cell etc. have been known. In addition, recently, the existence of fourth receptor is suggested. (Biochemistry Vol. 66, No. 3, pp. 218-231 (1994)).
Therefor, to antagonize PGE2 receptor means to suppress the effects above mentioned, so such an activity is linked to inhibit diuretic, to inhibit hyperlipemia, to inhibit reduce of blood sugar, to inhibit uterine contraction, to have analgesic action, to inhibit digestive peristalsis, to induce sleep. Therefor, PGE2 receptor antagonists are considered to be useful as anti-hyperlipemia, for the prevention of abortion, for analgesics, or as antidiarrheals or sleep inducer.
To agonize for PGE2 receptor means to promote the effects above mentioned, so such an activity is linked to have diuretic, to promote hypedipemia, to promote reduce of blood sugar, to contractile uterine, to promote digestive peristalsis, to suppress gastric acid secretion or to reduce blood pressure. Therefor, PGE2 receptor agonists are considered to be useful for diuretic, anti-diabetes, abortient, cathartics, antiulcer, anti-gastritis or antihypertensive.
In such a background, a lot of compounds which agonize or antagonize for PGE2 receptors have been proposed.
For example, in the specification of EP-0657422, it is disclosed that the compounds of the formula (A) 
wherein R1A is xe2x80x94COOR4A in which R4A is hydrogen or C1-4 alkyl,
xe2x80x94CONR5A R6A in which R5A and R6A each, independently, is hydrogen, C1-4 alkyl or C1-4 alkyl substituted by 1 of hydroxy or xe2x80x94CH2OH, 
in which AA is single bond or C1-4 alkylene or 
in which AA is 
in which mA is 0, 1, 2, 3, 4, nA is 0, 1, 2, 3, 4, and mA+nA is 2, 3, 4,
BA is xe2x80x94NR3ASO2xe2x80x94 or xe2x80x94SO2NR3Axe2x80x94 in which R3A is hydrogen, C1-4 alkyl or xe2x80x94CH2COOR7A in which R7A is hydrogen or R4aA, in which R4aA is C1-4 alkyl,
R2A is (i) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl,
(ii) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl substituted by 1, 2 or 3 of phenyl, C4-7 cycloalkyl or phenyl substituted by 1, 2 or 3 substituents selected from C1-4 alkyl, C1-4 alkoxy or halogen or
(iii) naphthyl,
in the formula 
or non-toxic salts thereof, are useful as PGE2 antagonist or agonist.
In the specification of EP-0578847 (corresponding to JP Patent Application Kokai Hei 6-25074), it is disclosed that the compounds of the formula (B) 
R1B is hydrogen or C1-4 alkyl,
R2B is hydrogen, C1-6 alkyl or phenyl,
R3B is
(i) C1-15 alkyl,
(ii) C1-8 alkyl substituted by 1 or 2 of benzene ring, C4-7 cycloalkyl or 4-7 membered monocyclic ring containing one nitrogen,
(iii) C10-15 fused tricyclic ring,
eB is an integer of 3-5,
fB is an integer of 1-3,
pB is 0 or an integer of 1-4,
qB is 0, 1 or 2,
sB is 0or an integer of 1-3;
with the proviso that, when 
xe2x80x83is (iii) or (iv), xe2x80x94(CH2)pBxe2x80x94 and xe2x95x90CHxe2x80x94(CH2)sBxe2x80x94 is bonded at the position a or b on the ring, and the ring in R3B may be substituted by one to three of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trihalomethyl, are useful as PGl2 agonist.
In the specification of JP Patent Application Kokai Sho 61-267532, it is disclosed that the compounds of the formula (D)
Ar1Dxe2x80x94XDxe2x80x94ArDxe2x80x94ZDxe2x80x94(RD)nDxe2x80x2xe2x80x83xe2x80x83(D)
wherein Ar1D is a nitrogen, sulfur or oxygen containing heterocyclic ring or an aromatic ring,
ArD is a phenyl or nitrogen, oxygen or sulfur containing heterocyclic ring,
Ar1D and Ar may be fully substituted or less than fully substituted by H, CH3, lower alkyl, aryl, aralkyl, halogen, hydroxy, lower alkoxy, CF3, COOH, alkylcarboxy, arylcarboxy, alkylcarbalkoxy, alkanoyl, formyl, oxo, nitrilo, amino, aminoalkyl, alkylamine, carboxyamide, aryloxy, nitro, sulfonyl, sulfonamide, thio, alkylthio, hydroxyalkyl or oxyalkylcarboxy,
XD is xe2x80x94O(CHR1D)nDxe2x80x94, xe2x80x94S(O)nDxe2x80x3xe2x80x94(CHR1D)nDxe2x80x94, xe2x80x94NR1D(CHR1D)nD-alkylene of up to 2 carbon atoms in the principal chain and up to a total 4 carbon atoms,
xe2x80x94C(R1D)xe2x95x90(CR1D)xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CO(CHR1D)nDxe2x80x2xe2x80x94, xe2x80x94CH(OH)xe2x80x94(CHR1D)nDxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94Sxe2x80x94, or xe2x80x94COxe2x80x94N(R1D)xe2x80x94,
ZD is an alkylene containing up to 10 carbon atoms in principal chain and a total of up to 12 carbon atoms and from 0 to 2 double bonds and the said alkylene chain may be attached to ArD through an oxygen, sulfur or amino nitrogen atom,
and when nDxe2x80x2 is 2 or more, one of the RD substituents may be halogen on an omega carbon of the alkylene chain ZD,
when nDxe2x80x2 is 1, RD is a substituent attached to one of the carbon atoms of ZD selected from the group consisting of oxo, OR3D, SR3D, N(R2D)2, R1D and xe2x80x94COR4D,
when nDxe2x80x2 is 2 or more, one RD is as previously defined, and the other RD is a substituent attached to one of the carbon atoms of ZD selected from the group consisting of oxo, OR3D, SR3D, N(R2D)2, xe2x80x94COR4D, lactone and halogen,
R1D is H or CH3,
R2D is H, lower alkyl, aryl or aralkyl,
R3D is H, lower alkyl, lower alkanoyl, aryl, aralkyl or substituted aryl in which the substituent is halogen, lower alkyl or lower alkoxy,
R4D is OR2D or N(R2D)2,
nD is 0 or 1,
nDxe2x80x2 is an integer of 1-7,
nDxe2x80x3 is 0, 1 or 2,
possess the anti-inflammatory and anti-allergic activity due to lipoxygenase inhibition.
In addition, in the specification of (E) U.S. Pat. No. 4,327,022, (F) JP Patent Application Kokai Sho 50-89352 and (G) U.S. Pat. No. 3,930,672, it is disclosed that the naphthol derivatives are useful as (1) cardiotonic or anti-bacterial agents, (2) analgesic, anti-inflammatory and antipyretic agent and (3) starting material of the compound related to copy paper, respectively.
The present inventors have been studding in order to find out PGE2 antagonist or agonist which have new skeleton in structure, and then have found out that the naphthyloxy acetic acid derivatives (compounds of the formula (I) as mentioned hereinafter) in which thioether, sulfinyl, sulfonyl, ether or amine are introduced into the side chain are useful as PGE2 antagonist or agonist, particularly, the mentioned compounds can bind the EP3 receptor strongly. And then, the present invention has been completed.
The compounds of the formula (A) as mentioned in Related Art possess xe2x80x94NR3ASO2xe2x80x94 or xe2x80x94SO2NR3A wherein all symbols are the same meaning as defined hereinbefore, in the side chain as basic structure. On the other hand, corresponding part in the present invention compounds is thioether, sulfinyl, sulfonyl, ether or amine.
The compounds of the formula (B), (D) and the compounds described in (E), (F) and (G) as mentioned in Related Art possess (1) PGI2 agnostic activity, (2) anti-inflammatory and anti-allergic activity due to lipoxygenase inhibition (3) cardiotonic or anti-bacterial agents, (4) analgesic, anti-inflammatory and antipyretic agent and (5) starting material of the compound related to copy paper, respectively. On the other hand, the present invention compounds possess the PGE2 antagonistic or agnostic activity.
That is to say, the present invention provides:
1) a naphthyloxyacetic acid derivative of the formula (I) 
wherein A is
(i) hydrogen,
(ii) xe2x80x94(C1-4 alkylene)xe2x80x94COOR1 in which R1 is hydrogen or C1-4 alkyl,
(iii) xe2x80x94(C1-4 alkylene)xe2x80x94CONR2R3 in which R2 and R3 each, independently, is hydrogen or C1-4 alkyl,
(iv) xe2x80x94(C1-4 alkylene)xe2x80x94OH,
(v) xe2x80x94(C1-4 alkylene)-tetrazolyl or
(vi) xe2x80x94(C1-4 alkylene)xe2x80x94CN;
E is
(i) single bond or
(ii) C1-6 alkylene;
G is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94NR4xe2x80x94 in which, R4 is hydrogen or C1-4 alkyl;
L is
(i) C1-6 alkylene,
(ii) xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94 in which m is 0 or an integer of 1-3, n is 0 or an integer of 1-3 or
(iii) xe2x80x94(CH2)xxe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94 in which x is an integer of 1-3, y is 0 or an integer of 1-3; 
in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl;
in the formula 
with the proviso that,
(1) when G is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, M is neither 
in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,
(2) when m in L is 0, G is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94,
(3) when n in L is 0, M is 
in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,
(4) when y in L is 0, M is 
in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl,
(5) when A is hydrogen, L is xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94 in which m and n are the same meaning as hereinbefore defined, or xe2x80x94(CH2)xxe2x80x94CH(OH)xe2x80x94(CH2)y in which x and y are the same meaning as hereinbefore defined, and
(6) tetrazolyl in A is 
or non-toxic salt thereof, non-toxic acid addition salt thereof or their hydrate,
2) a compound described in 1), wherein A is xe2x80x94(C1-4 alkylene)xe2x80x94COOR1,
3) a compound described in 1), wherein A is xe2x80x94(C1-4 alkylene)xe2x80x94CONR2R3, xe2x80x94C1-4 alkylene)xe2x80x94OH, xe2x80x94(C1-4 alkylene)-tetrazolyl or xe2x80x94(C1-4 alkylene)xe2x80x94CN,
4) a compound described in 1), wherein A is hydrogen,
5) a compound described in 1)-5), wherein L is xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)n or xe2x80x94(CH2)xxe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94,
6) a compound described in 5), wherein G is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94,
7) a compound described in 5), wherein G is xe2x80x94Oxe2x80x94,
8) a compound described in 5), wherein G is xe2x80x94NR4xe2x80x94,
9) a compound described in 6), which is
(1) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2RS-propanol,
(2) 1-[2-(5-hydroxy-1-naphthyl)ethylsulfinyl]-3-phenoxy-2RS-propanol,
(3) 1-[2-(5-hydroxy-1-naphthyl)ethylsulfonyl]-3-phenoxy-2RS-propanol,
(4) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2R-propanol,
(5) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2S-propanol,
(6) 1-(5-hydroxy-1-naphthyl)methylthio-3-phenoxy-2RS-propanol,
(7) 1-(5-hydroxy-1-naphthyl)methylsulfinyl-3-phenoxy-2RS-propanol,
(8) 1-(5-hydroxy-1-naphthyl)methylsulfonyl-3-phenoxy-2RS-propanol,
(9) 2-[3-(5-hydroxy-1-naphthyl)propylthio]-1-phenyl-1RS-ethanol,
(10) 2-[3-(5-hydroxy-1-naphthyl)propylsulfinyl]-1-phenyl-1RS-ethanol,
(11) 2-[3-(5-hydroxy-1-naphthyl)propylsulfonyl]-1-phenyl-1RS-ethanol,
(12) 1-(5-hydroxy-1-naphthyl)thio-3-phenoxy-2RS-propanol,
(13) 1-(5-hydroxy-1-naphthyl)sulfinyl-3-phenoxy-2RS-propanol,
(14) 1-(5-hydroxy-1-naphthyl)sulfonyl-3-phenoxy-2RS-propanol,
(15) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-chlorophenoxy)-2RS-propanol,
(16) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methylphenoxy)-2RS-propanol,
(17) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methoxyphenoxy)-2RS-propanol,
(18) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-diphenylmethoxy-2RS-propanol,
(19) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-[1-phenyl-1-(4-chlorophenyl)methoxy]-2RS-propanol,
(20) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenylthio-2RS-propanol,
(21) 1-(5-hydroxy-1-naphthyl)methylthio-3-diphenylmethoxy-2RS-propanol,
(22) 1-(5-hydroxy-1-naphthyl)methylthio-3-[1-phenyl-1-(4-chlorophenyl)methoxy]-2RS-propanol,
(23) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(24) 2-{5-[2-(2RS -hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(25) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(26) 2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(27) 2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(28) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]acetic acid methyl ester,
(29) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]acetic acid methyl ester,
(30) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]acetic acid methyl ester,
(31) 2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic acid methyl ester,
(32) 2-{5-[3-(2RS-hydroxy-2-phenylethylsulfinyl)propyl]-1-naphthyloxy}acetic acid methyl ester,
(33) 2-{5-[3-(2RS-hydroxy-2-phenylethylsulfonyl)propyl]-1-naphthyloxy}acetic acid methyl ester,
(34) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid methyl ester,
(35) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic acid methyl ester,
(36) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]acetic acid methyl ester,
(37) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid methyl ester,
(38) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid methyl ester,
(39) 2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(40) 2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(41) 2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(42) 2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(43) 2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(44) 2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}acetic acid methyl ester,
(45) 2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]acetic acid methyl ester,
(46) 2-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]methyl-1-naphthyloxy}acetic acid methyl ester,
(47) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-acetic acid,
(48) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl-1-naphthyloxy}acetic acid,
(49) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}acetic acid,
(50) 2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid,
(51) 2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid,
(52) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]acetic acid,
(53) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]acetic acid,
(54) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]acetic acid,
(55) 2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic acid,
(56) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid,
(57) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic acid,
(58) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]acetic acid,
(59) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid,
(60) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid,
(61) 2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid,
(62) 2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid,
(63) 2-{5-[2-(2RS-hydroxy-3-(4-methyoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}acetic acid,
(64) 2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}acetic acid,
(65) 2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}acetic acid,
(66) 2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]acetic acid,
(67) 1-cyanlomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]naphthalene,
(68) 1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-chlorophenoxy)propylthio]ethyl}naphthalene,
(69) 1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methylphenoxy)propylthio]ethyl}naphthalene,
(70) 1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methoxyphenoxy)propylthio]ethyl}naphthalene,
(71) 1-cyanomethoxy-5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]naphthalene,
(72)1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]naphthalene,
(73) 1-cyanomethoxy-5-(2RS-hydroxy-3-diphenylmethoxypropylthiomethyl)naphthalene,
(74) 2-{5-[2-(2RS -hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)ethyl]-1-naphthyloxy}ethanol,
(75) 2-{5-[2-(2RS-hydroxy-3-phenylaminopropylthio)ethyl]-1-naphthyloxy}ethanol,
(76) 1-(tetrazol-5-ylmethoxy)-5-{2-{2RS-hydroxy-3-(4-methyoxyphenoxy)propylthio]ethyl}naphthalene,
(77) N-methyl-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]methyl-1-naphthyloxy}acetic acid amide,
(78) 1-{2-[5-hydroxy-1-(1,2,3,4-tetrahydronaphthyl)]ethylthio}-3-phenoxy-2RS-propanol,
(79) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydronaphthyloxy)}acetic acid methyl ester,
(80) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydronaphthyloxy)}acetic acid or
(81) 1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-5,6,7,8-tetrahydronaphthalene,
10) a compound described in 7), which is
(1) 1-[2-(5-hydroxy-1-naphthyl)ethoxy]-3-phenoxy-2RS-propanol,
(2) 2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic acid methyl ester or
(3) 2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic acid,
11) a compound described in 8), which is
(1) 1-[2-(5-hydroxy-1-naphthyl)ethylamino]-3-phenoxy-2RS-propanol or
(2) 2-{5-[2-(2RS-hydroxy-3-pheoxypropylamino)ethyl]-1-naphthyloxy}acetic acid,
12) a pharmaceutical composition which comprises a naphthyloxyacetic acid derivative of the formula (I) depicted in 1), non-toxic salt thereof, non-toxic acid addition salt thereof or their hydrate as an active ingredient, and
13) a pharmaceutical composition (PGE2 antagonist or agonist) which comprises a naphthyloxyacetic acid derivative of the formula (I) depicted in 1), non-toxic salt thereof, non-toxic acid addition salt thereof or their hydrate as an active ingredient.
In the formula (I), C1-4 alkyl represented by R1, R2, R3 and R4, or C1-4 alkyl represented as substituent of phenyl in M means methyl, ethyl, propyl, butyl and isomeric groups thereof.
In the formula (I), C1-4 alkylene in A means methylene, ethylene, trimethylene, tetramethylene and isomeric groups thereof.
In the formula (I), C1-6 alkylene represented by E and L means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and isomeric groups thereof.
In the formula (I), 1-4 alkoxy in M means methoxy, ethoxy, propoxy, butoxy and isomeric groups thereof.
In the formula (I), halogen in M means chlorine, bromine, fluorine and iodine.
In the formula (I), the side chain represented by xe2x80x94Oxe2x80x94A may be connected with any carbon atom at 1st to 4th position, preferably, at 1st position.
In the formula (I), the side chain represented by xe2x80x94Exe2x80x94Gxe2x80x94Lxe2x80x94M may be connected with any carbon atom at 5th to 8th position, preferably, at 5th or 6th position.
Unless otherwise, specified all isomers are included in the invention. For example, alkyl, alkylene and alkenylene includes straight-chain or branched-chain ones. Double bond in alkenylene include structure of configurations E, Z and EZ mixtures. Isomers generated by asymmetric carbon(s) e.g. branched alkyl are also included in the present invention. In addition, isomers generated by sulfinly are also included in the present invention.
Salts
The compounds of the present invention of the formula (I) may be converted into the corresponding salts by known methods per se. Non-toxic and water-soluble salts are preferable. Suitable salts, for example, are follows. salts of alkaline metals (potassium, sodium etc.), salts of alkaline earth metals (calcium, magnesium etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine etc.).
Acid Addition Salts
The compounds of the formula (I) may be converted into the corresponding acid additional salts by methods known per se. Non-toxic and water-soluble acid addition salts are preferable. Suitable acid addition salts, for example, are salts of inorganic acids, e.g., hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, nitrate etc., or salts of organic acids, e.g., acetate, trifluoroactate, lactate, tartarate, oxalate, fumarate, maleate, citrate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, toluenesulphonate, isethioate, glucuronate, gluconate etc.
Preferable Compound
In the compounds of the formula (I) of the present invention, the compounds wherein L is xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94 in which m and n are the same meaning as hereinbefore defined, or xe2x80x94(CH2)xxe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94 in which x and y are the same meaning as hereinbefore defined, are preferable. The compounds wherein L is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94, are more preferable.
Concretely, the following compounds are preferable.
The compounds of the formula (IA) 
The compounds of the formula (IB) 
The compounds of the formula (IC) 
The compounds of the formula (ID) 
The compounds of the formula (IE) 
The compounds of the formula (IF) 
The compounds of the formula (IG) 
The compounds of the formula (IH) 
The compounds of the formula (IJ) 
The compounds of the formula (IK) 
The compounds of the formula (IL) 
The compounds of the formula (IM) 
The compounds of the formula (IN) 
The compounds of the formula (IO) 
In the formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (IM), (IN) and (IO), all symbols are the same meaning as hereinbefore defined.
The compounds described in Example and the following compounds are preferable particularly.
In the compounds of the formula (I) of the present invention, the compounds of the formula (I-1) 
wherein all symbols are the same meaning as hereinbefore defined
may be prepared by the following methods (a)-(b).
(a) In the compounds of the formula (I-1) of the present invention, the compounds wherein L is xe2x80x94(CH2)xxe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94 or C1-6 alkylene, i.e., the compounds of the formula (I-1a) 
wherein La is xe2x80x94(CH2)xxe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94 or C1-6 alkylene, and the other symbols are the same meaning as hereinbefore defined
may be prepared from the compounds of the formula (II-a) 
wherein Laa is xe2x80x94(CH2)xxe2x80x94CH(ORaa)xe2x80x94(CH2)yxe2x80x94 in which, Raa is the protecting group which may be removed in an acidic condition, for example, tetrahydropyranyl etc., or C1-6 alkylene, Ra is the protecting group which may be removed in an acidic condition or an alkaline condition, for example, methoxymethyl or ethylcarbonate etc., and the other symbols are the same meaning as hereinbefore defined, with the proviso that when nitrogen atom in G or M in the formula (I-1a) is free xe2x80x94NH group, NH group in the formula (II-a) is protected by the well-known protecting group (for example, benzyloxycarbonyl (cbz), t-butoxycarbonyl (boc) or trifluoroacetyl (COCF3)etc.)
by removal of hydroxy-protecting group in an acidic condition, or removal of hydroxy-protecting group in an acidic condition and an alkaline condition two times, succeedingly, (Which reaction may be started first.), if necessary, followed by removal of NH-protecting group.
This reaction may be carried out by known methods. For example, the removal of hydroxy-protecting group in an acidic condition may be carried out in a water-miscible organic solvent (methanol, ethanol, tetrahydrofuran (THF) etc.), by using organic acid (acetic acid, p-toluene sulfonic acid, trifluoro acetic acid or trichloro acetic acid etc.) or inorganic acid (hydrochloric acid or hydrobromic acid etc.), at 0-90xc2x0 C. The removal of hydroxy-protecting group in an alkaline condition may be carried out in an organic solvent (methanol, ethanol, dimethoxyethane or mixture thereof etc.), using an aqueous solution of hydroxide of alkali (sodium hydroxide, potassium hydroxide etc.), hydroxide of alkaline-earth metals (calcium dihydroxide etc.) or carbonate (potassium carbonate etc.) at 0-50xc2x0 C.
As for removal of NH-protecting group, for example, the removal of cbz group may be carried out under an atmosphere of hydrogen gas, in an organic solvent (methanol, ethanol or THF etc.), by using catalyst (Pdxe2x80x94C, Pd or Ni etc.), at 0-50xc2x0 C. The removal of boc may be carried out in a water-miscible organic solvent (methanol, ethanol or THF etc.), by using organic acid (acetic acid, p-toluene sulfonic acid, trifluoro acetic acid or trichloro acetic acid etc.) or inorganic acid (hydrochloric acid or hydrobromic acid etc.), at 0-90xc2x0 C. The removal of COCF3 may be carried out, for example, in a water-miscible organic solvent (methanol, ethanol, THF, dimethoxyethane or mixture thereof etc.), using an aqueous solution of hydroxide of alkali (sodium hydroxide, potassium hydroxide etc.), hydroxide of alkaline-earth metals (calcium dihydroxide etc.) or carbonate (potassium carbonate etc.) at 0-50xc2x0 C.
(b) In the present invention compounds of the formula (I-1), the compounds wherein L is xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94, i.e., the compounds of the formula (I-1b) 
wherein Lb is xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94, and the other symbols are the same meaning as hereinbefore defined
may be prepared from the compounds of the formula (II-b) 
wherein Lbb is xe2x80x94(CH2)mxe2x80x94CH2CH(ORb)xe2x80x94(CH2)nxe2x80x94 in which, Rb is the well-known elimination group (for example, mesyl or tosyl group etc.), and the other symbols are the same meaning as hereinbefore defined, with the proviso that when nitrogen atom in G or M in the formula (I-1b) is free xe2x80x94NH group, NH group in the formula (II-b) is protected by the well-known protecting group (for example, cbz, boc or COCF3 etc.)
by removal of elimination group, if necessary, followed by removal of NH-protecting group.
This reaction may be carried out in an organic solvent (methanol or ethanol etc.) by adding base (potassium hydroxide, sodium hydroxide or triethylamine etc.) at 0-100xc2x0 C. The removal of NH-protecting group may be carried out by the method described hereinbefore.
In the compound of the formula (I) of the present invention, the compounds of the formula (I-2) of the present invention 
wherein A2 is the same meaning as A other than hydrogen
may be prepared by reacting the compounds, in which nitrogen atom in G or M in the formula (I-1) is free xe2x80x94NH group, NH group is protected by the well-known protecting group (for example, cbz, boc or COCF3 etc.), i.e. the compounds of the formula (II-c) 
wherein Ga and Ma are the same meaning as G and M, respectively, with the proviso that when nitrogen atom in G or M in the formula (I-2) is free xe2x80x94NH group, NH group is protected by the well-known protecting group (for example, cbz, boc or COCF3 etc.) and the other symbols are the same meaning as hereinbefore defined
with the compounds of the formula (III) 
wherein X2 is halogen and A2a is
(i) xe2x80x94(C1-4 alkylene)xe2x80x94COOR1a in which R1a is C1-4 alkyl,
(ii) xe2x80x94(C1-4 alkylene)xe2x80x94OR5, in which R5 is tetrahydropyranyl,
(iii) xe2x80x94(C1-4 alkylene)xe2x80x94CONR2R3,
(iv) xe2x80x94(C1-4 alkylene)-tetrazolyl or
(v) xe2x80x94(C1-4 alkylene)xe2x80x94CN,
and the other symbols are the same meaning as hereinbefore defined, with the proviso that when nitrogen atom in A2a is free xe2x80x94NH group, NH group is protected by the well-known protecting group (for example, cbz, boc or COCF3 etc.),
if necessary, followed by hydrolysis in an alkaline condition or by removal of protecting group.
The above mentioned O-alkylation is known, and for example, this reaction may be carried out in a water-miscible organic solvent (acetone, THF or methylene chloride etc.) in the presence of a base (potassium carbonate etc.), at 0-50xc2x0 C.
The hydrolysis in an alkaline condition is well known. For example, this reaction may be carried out in a water-miscible organic solvent (methanol, ethanol, dimethoxyethane or mixture thereof etc.), using an aqueous solution of hydroxide of alkali (sodium hydroxide, potassium hydroxide etc.), hydroxide of alkaline-earth metals (calcium dihydroxide etc.) or carbonate (potassium carbonate etc.) at 0-50xc2x0 C. The removal of protecting group may be carried out by the method described hereinbefore.
In the compounds of the formula (I) of the present invention, the compounds wherein A is xe2x80x94(C1-4 alkylene)-tetrazol-5-yl, i.e. the compounds of the formula (I-3) 
in which, A3 is xe2x80x94(C1-4 alkylene)-tetrazol-5-yl and the other symbols are the same meaning as hereinbefore defined
may be also prepared by reacting the compounds of the formula (I-4) 
in which A4 is xe2x80x94(C1-4 alkylene)xe2x80x94CN and the other symbols are the same meaning as hereinbefore defined
with the azide.
The reaction to introduce a tetrazol-5-yl group from cyano group with an azide are known, it may be carried out, for example, on anhydrous condition, using with azide (sodium azide, lithium azide, potassium azide etc.) in the presence of weak acid (pyridium chloride, ammonium chloride, dimethylaniline hydrochloride etc.) in an inert organic solvent (DMF, N-methylpyrrolidone etc.) with heating.
In the compounds of the formula (I) of the present invention, the compounds wherein A is xe2x80x94(C1-4 alkylene)xe2x80x94CONR2R3, i.e. the compounds of the formula (I-5) 
in which, A5 is xe2x80x94(C1-4 alkylene)xe2x80x94CONR2R3 in which R2 and R3 are the same meaning as hereinbefore defined and the other symbols are the same meaning as hereinbefore defined
may be also prepared by reacting the compounds of the formula (I-6) 
in which A6 is xe2x80x94(C1-4 alkylene)xe2x80x94COOR1a in which R1a is the same meaning as hereinbefore defined and the other symbols are the same meaning as hereinbefore defined
with the compounds of the formula
HNR2R3xe2x80x83xe2x80x83(IX)
in which all symbols are the same meaning as hereinbefore defined.
The above reaction to form an amide bond is well known. For example, this reaction may be carried out in inert organic solvent (benzene, toluene or methylene chloride etc.), or in the absence of solvent, using tertiary amine (pyridine or triethylamine etc.) at 0-50xc2x0 C., or it may be carried out in an organic solvent (methylene chloride or THF etc.), using a corresponding base, in the presence or absence of corresponding condensing agents (2-chloro-N-methylpyridiunium iodide etc.) at 0-40xc2x0 C.
The compounds of the formula (II-a) and (II-b) may be prepared by the known reaction. For example, these compounds may be prepared according to the method shown in the reaction scheme (1), (2), (3) or (4) or method described in Example.
In the compounds of the formula (I-1) of the present invention, the compounds wherein G is xe2x80x94NHxe2x80x94 and L is xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94, i.e. the compounds of the formula 
in which Ld is xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94 in which y is the same meaning as hereinbefore defined and the other symbols are the same meaning as hereinbefore defined
may be also prepared according to the method shown in the reaction scheme (5) or method described in Example.
In the compounds of the formula (I) of the present invention, the compounds wherein M is 
in which each phenyl may be substituted by the substituent described hereinbefore and L is xe2x80x94(CH2)xxe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94, i.e. the compounds of the formula 
in which Mb is 
in which each phenyl may be substituted by the substituent described hereinbefore, Le is xe2x80x94(CH2)xxe2x80x94CH(OH)xe2x80x94(CH2)yxe2x80x94 in which x and y are the same meaning as hereinbefore defined, G3 is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94NR4xe2x80x94 and the other symbols are the same meaning as hereinbefore defined
may be also prepared according to the method shown in the reaction scheme (6) or method described in Example.
In reaction scheme (1), (2), (3), (4), (5) and (6) each symbol means the following definition or is the same meaning as defined hereinbefore.
Et is ethyl,
Ac is acetyl,
iPr is isopropyl.
Ph is phenyl,
MOM is methoxymethyl,
9-BBN is 9-borabicyclo[3.3.1]nonan,
LAH is lithium aluminum hydride,
TsCl is tosylchloride,
AcSK is potassium thioacetate,
mCPBA is methachloroperbenzoic acid,
cbz is benzyloxycarbonyl,
Lc is Laa, Lbb or C1-6 alkylene,
Ec is C1-6 alkylene,
G1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, or xe2x80x94SO2xe2x80x94,
G2 is xe2x80x94NR4xe2x80x94,
Bu4NBr is tetrabutylammonium bromide,
Py is pyridine,
Rd is
1) acetyl or hydrogen when G3 is xe2x80x94Sxe2x80x94,
2) hydrogen when G3 is xe2x80x94Oxe2x80x94 or xe2x80x94NR4axe2x80x94 in which R4a is C1-4 alkyl,
3) NH-protecting group as defined hereinbefore when G3 is xe2x80x94NHxe2x80x94Z is NH-protecting group as defined hereinbefore and
Pha is phenyl may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl.
The compounds of the formula (II-a) are a part of the compounds of the formula (VII).
The compounds of the formula (II-b) are a part of the compounds of the formula (VIII). The compounds of the formula (IV), (Vxe2x80x94O) or (VI) as starting materials may be prepared by the known methods. For example, these compound may be prepared by the methods described in Example in the present specification.
In each reaction in the present specification, obtained products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
The other starting materials and reagents in the present invention are known per se or may be prepared by known methods. 
The compounds of the present invention of the formula (I) are useful as PGE2 antagonists or agonists, because they can bind onto prostaglandin E2 receptors and have antagonist or agonist activity against the action thereof.
As mentioned hereinbefore, to antagonize PGE2 receptor is linked to inhibit diuretic, to inhibit hyperlipemia, to inhibit reduce of blood sugar, to inhibit uterine contraction, to have analgesic action, to inhibit digestive peristalsis, to induce sleep. Therefor, PGE2 antagonists are considered to be useful as anti-hyperlipemia, for the prevention of abortion, for analgesics, or as antidiarrheals or sleep inducer.
As mentioned hereinbefore, to agonize for PGE2 receptor is liked to promote diuretic, to promote hyperlipemia, to promote reduce of blood sugar, to contractile uterine, to promote digestive peristalsis, to suppress gastric acid secretion or to reduce blood pressure. Therefor, PGE2 receptor agonists are considered to be useful for diuretic, anti-diabetes, abortient, cathartics, antiulcer, anti-gastritis or antihypertensive.
For example, in standard laboratory test, the effects of the compounds of the present invention were confirmed by inhibitory effect on binding PGE2 using expression cell of receptor.
(I) Binding Assay using Expression Cell of Prostanoide Receptor Subtype
The preparation of membrane fraction was carried out according to the method of Sugimoto et al (J. Biol. Chem. 267, 6463-6466 (1992)), using expression CHO cell of prostanoide receptor subtype (mouse EP3xcex1).
The standard assay mixture contained membrane fraction (0.5 mg/ml), [3H]-PGE2 in a final volume of 200 ml was incubated for 1 hour at room temperature. The reaction was terminated by addition of 3 ml of ice-cold buffer. The mixture was rapidly filtered through a glass filter (GF/B). The radioactivity associated with the filter was measured by liquid scintillation counting.
Kd and Bmax values were determined from Scatchard plots (Ann. N.Y. Acad. Sci., 51, 660 (1949)). Non-specific binding was calculated as the bond in the presence of an excess (2.5 nM) of unlabeled PGE2. In the experiment for competition of specific [3H]-PGE2 binding by the compounds of the present invention, [3H]-PGE2 was added at a concentration of 2.5 nM and the compounds of the present invention were at a concentration of 1 mM. Buffer: 10 mM potassium phosphate (pH6.0), 1 mM EDTA, 10 mM MgCl2, 0.1 M NaCl.
The dissociation constant Ki (xcexcM) of each compound was calculated by the following equation.
Ki =IC50/(1+([C]/Kd))
The results were shown as follows.
The toxicity of the compounds of the present invention are very low and therefore, it is confirmed that these compounds are safe for use as medicine.
The compounds of the formula (I) of the present invention are useful for PGE2 antagonists or agonists, because they can bind onto PGE2 receptors and have an activity to antagonize or agonize for the action thereof.
As mentioned hereinbefore, to antagonize PGE2 is linked to inhibit hyperlipemia, to inhibit uterine contraction, to have analgesic action, to inhibit digestive peristalsis or to induce sleep. Therefor, PGE2 antagonists are considered to be useful as anti-hyperlipemia, for the prevention of abortion, for analgesics, or as antidiarrheals or sleep inducer.
As mentioned hereinbefore, to agonize PGE2 is linked to promote diuretic, to promote reduce of blood sugar, to contractile uterine, to promote digestive peristalsis, to suppress gastric acid secretion or to reduce blood pressure. Therefor, PGE2 agonists are useful for diuretics, anti-diabete abortient, cathartics, antiulcer, anti-gastritis or antihypertensive.
For the purpose above described, the compounds of the formula (I), non-toxic salts thereof and hydrates thereof may be normally administered systematically or partially, usually by oral or parenteral administration.
The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 xcexcg and 100 mg, by oral administration, up to several times per day, and between 0.1 xcexcg and 10 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hours per day into vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
On administration of the compounds of the present invention, it is used as solid compositions, liquid compositions or other compositions for oral administration, as injections, liniments or suppositories etc. for parenteral administration.
Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules etc.
Capsules contain hard capsules and soft capsules.
In such solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent such as lactose, mannitol, mannit, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate. The compositions may also comprise, as is normal practice, additional substances other than inert diluents: e.g. lubricating agents such as magnesium stearate, disintegrating agents such as cellulose calcium glycolate, and assisting agents for dissolving such as glutamic acid or asparaginic acid. The tablets or pills may, if desired, be coated with film of gastric or enteric material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (for example, purified water, ethanol etc.). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening agents, flavouring agents, perfuming agents and preserving agents.
Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s). Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give the title compound isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 may be used.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol such as ethanol, POLYSOLBATE80 (registered trade mark) etc. Such compositions may comprise additional diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents such as assisting agents for dissolving (for example, glutamic acid, asparaginic acid). They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluents for injection immediately before used.
Other compositions for parenteral administration include liquids for external use, and endemic liniments, ointment, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by know methods.